PROJECT SUMMARY Substance abuse and misuse pose significant costs to society and represent a global disease burden. Relapse after a period of drug-free abstinence is one of the most profoundly debilitating aspects of addiction, occurring in 40?80% of individuals. Understanding the neurobiological mechanisms of drug taking and relapse will ultimately lead to better therapeutic interventions. The ventral striatum is a network of brain structures implicated in compulsive drug-seeking and includes the ventral pallidum, nucleus accumbens (NAc), and olfactory tubercle (OT). The OT, like the NAc, is a site of massive innervation of dopaminergic neuron terminals from the ventral tegmental area in the midbrain. Rodents self-administer psychoactive substances and electrical current into the OT, and more readily administer cocaine into the OT than even NAc. Further, our lab has uncovered that the activity of OT neurons robustly reflects reward-guided behaviors and rewards. Despite this evidence pointing towards a role for the OT in mediating reinforcement, little is known about the OT, and at present, the OT is not included in mainstream models of the reward system. The short-term goal of this project is to build off both our published and unpublished studies positioning the OT in the reward circuitry to determine mechanisms whereby the OT exerts control over cocaine seeking and taking. Our overall hypothesis is that there is a functional organization amongst ventral striatum subregions which influences drug seeking. There are three aims to be executed by our collaborative team of experts in addiction neurobiology, synaptic neurobiology, and in vivo physiology and behavior. First, we will use brain slice recordings to determine the circuitry which connects the OT with the ventral tegmental area and ventral striatum structures. Second, we will use in vivo physiological methods to demonstrate manners whereby OT neurons, including OT medium spiny neurons, represent drug seeking. Finally, we will employ cell-specific optogenetic methods to determine the regulation of reinforcement and drug-seeking by OT neurons. The results of this project will answer long-standing questions about the fundamental circuitry of the OT and its significance in the context of motivated behavior and drug-seeking. Together this project will contribute to our long-term goal of generating a more complete model of the brain?s reward system.